Study conduct, monitoring and data management in a trinational trial: the OPTIMA model.

The OPTions In Management with Antiretrovirals (OPTIMA) Trial, a collaboration between three governmental agencies in the USA, UK and Canada is a large-scale, multicenter, randomized controlled trial designed to compare the relative efficacy of different therapeutic strategies in HIV disease. The collaboration of three coordinating centers introduced unique data management issues including: a) use of different data systems for managing "country" trial data; b) two-way data transfer between the coordinating centers and the center where OPTIMA data is merged and analysis files are generated; and c) translation of certain data forms (mainly patient completed questionnaires) into French and Spanish. The involvement of three data centers provided a challenge in planning, designing and executing data management procedures in OPTIMA.

Vestibular symptoms and signs are correlated with abnormal neurogenic vestibular evoked potentials in patients with multiple sclerosis.

Objectives: Symptoms of disequilibrium in multiple sclerosis (MS) are common. Neurogenic vestibular evoked potentials (NVsEPs) are saccular responses to tone-pip acoustic stimuli and are recordable from the parietal areas ipsilaterally to the stimulated ear. We wished to determine possible correlations of abnormal findings in NVsEP with clinical neurological findings related to the vestibular system, and demyelination seen on MRI.

Morphological methods in the diagnosis of mitochondrial encephalomyopathies: the role of electron microscopy.

Mitochondrial encephalomyopathies (MEs) encompass a heterogeneous group of disorders that frequently present a diagnostic challenge to clinicians. Historically, MEs were diagnosed by finding ragged red fibers in the muscle biopsy and confirmatory evidence was provided by the presence of numerical and/or ultrastructural abnormalities in mitochondria. In most centers diagnosis involves clinical evaluation and the morphological, histochemical, and biochemical investigation of a skeletal muscle biopsy.

Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations.

We describe clinical, electrophysiological, histopathological and molecular features of a unique disease caused by mutations in the glycyl-tRNA synthetase (GARS) gene. Sixty patients from five multigenerational families have been evaluated. The disease is characterized by adolescent onset of weakness, and atrophy of thenar and first dorsal interosseus muscles progressing to involve foot and peroneal muscles in most but not all cases.

Proteolysis of cell-surface tissue transglutaminase by matrix metalloproteinase-2 contributes to the adhesive defect and matrix abnormalities in thrombospondin-2-null fibroblasts and mice.

Thrombospondin (TSP)-2-null dermal fibroblasts display an attachment defect that results from increased matrix metalloproteinase (MMP)-2 levels in their conditioned media. To investigate the molecular mechanisms responsible for this defect, we analyzed the activity of tissue transglutaminase (tTG) in TSP-2-null dermal fibroblasts and in tissues of TSP-2-null mice. tTG functions as a co-receptor for beta1 and beta3 integrins and stabilizes extracellular matrix proteins by introduction of isopeptide cross-links.

A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

Background: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults.

Methods: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine").

SPARC-thrombospondin-2-double-null mice exhibit enhanced cutaneous wound healing and increased fibrovascular invasion of subcutaneous polyvinyl alcohol sponges.

Secreted protein acidic and rich in cysteine (SPARC) and thrombospondin-2 (TSP-2) are structurally unrelated matricellular proteins that have important roles in cell-extracellular matrix (ECM) interactions and tissue repair. SPARC-null mice exhibit accelerated wound closure, and TSP-2-null mice show an overall enhancement in wound healing. To assess potential compensation of one protein for the other, we examined cutaneous wound healing and fibrovascular invasion of subcutaneous sponges in SPARC-TSP-2 (ST) double-null and wild-type (WT) mice.

Neurogenic vestibular evoked potentials in three cases of vestibular system dysfunction.

Objectives: To demonstrate that neurogenic vestibular evoked potentials (NVsEP) may be specific to the vestibular system using three cases of vestibular system dysfunction and normal auditory function,

Methods: Neurogenic vestibular evoked potentials were performed by recording from the parietal areas of the scalp using a tone-pip auditory stimulus via headphones. Brainstem auditory evoked potentials (BAEPs) and NVsEP were performed in all three cases.

Results: Brainstem auditory evoked potentials were within normal limits in all three cases.

The CC chemokine ligand, CCL2/MCP1, participates in macrophage fusion and foreign body giant cell formation.

The foreign body reaction (FBR) develops in response to the implantation of almost all biomaterials and can be detrimental to their function. The formation of foreign body giant cells (FBGC), which damage the surface of biomaterials, is considered a hallmark of this reaction. FBGC derive from blood-borne monocytes that enter the implantation site after surgery in response to the release of chemotactic signals.

Reversible inflammatory and vacuolar myopathy with vitamin E deficiency in celiac disease.

We report a patient with late-onset celiac disease and neurological manifestations including myopathy, polyneuropathy, and ataxia. Laboratory investigations showed anti-gliadin antibodies and severe vitamin E deficiency. Muscle biopsy revealed inflammatory infiltrates and rimmed vacuoles, similar to those found in inclusion-body myositis.

Neurogenic vestibular evoked potentials in the diagnosis of multiple sclerosis.

Objectives: To determine the value of neurogenic vesibular evoked potential (NVESTEP) studies in comparison with other paraclinical tests in demonstrating dissemination in time and space in Multiple Sclerosis (MS) and in identifying clinically silent lesions.

Method: All patients in whom MS was suspected but the diagnosis of MS was not possible based on the McDonald criteria were included in this study. We studied 14 patients and performed visual, brainstem auditory, somatosensory and neurogenic vestibular evoked potentials in all patients, together with MRI and CSF analysis of oligoclonal bands (OB).

A novel PMP22 mutation Ser22Phe in a family with hereditary neuropathy with liability to pressure palsies and CMT1A phenotypes.

We describe a Cypriot family in which some family members presented with episodes of pressure palsies, while other family members had a slowly progressive chronic polyneuropathy typical of the Charcot-Marie-Tooth type 1 phenotype. All family members were evaluated clinically, with nerve conduction studies, and with genetic testing. In all affected individuals there was clinical and electrophysiological evidence of diffuse demyelinating sensorimotor polyneuropathy and a novel point mutation in the PMP22 gene (Ser22Phe) was identified.

A novel movement disorder of the lower lip.

Four patients, aged 25 to 42 years presented with acute onset of a movement disorder characterized by a tonic, sustained, lateral and outward protrusion of one half of the lower lip. The movement disorder was present at rest, while in some patients, it was also present during speech. In all cases, the abnormal lip posture could be suppressed voluntarily.

Neurogenic vestibular evoked potentials using a tone pip auditory stimulus.

Objectives: To obtain neurogenic vestibular evoked potentials (NVESTEPs) with surface scalp recording using a tone pip auditory stimulus.

Methods: Fourteen neurologically normal volunteers (Age range 26-45 years, 10 females and 4 males), and two patients with sensorineural hearing loss and possible multiple sclerosis respectively, were examined. Two channel recordings were obtained, the first channel being P3 referred to Fpz, and the second channel being P4 referred to Fpz.

The role of thrombospondins 1 and 2 in the regulation of cell-matrix interactions, collagen fibril formation, and the response to injury.

Thrombospondins (TSPs) 1 and 2 are extracellular modular glycoproteins that are best known for their anti-angiogenic properties and their ability to modulate cell-matrix interactions. However, these proteins, and in particular TSP2, are pleiotropic in function and affect processes as disparate as bone growth and hemostasis. In recognition of their ability to influence a wide variety of cell functions, and in the absence of convincing evidence for their participation as integral components of extracellular structures, the term 'matricellular' has been applied to these and a small group of functionally related proteins.

Thrombospondin 2 levels are increased in aged mice: consequences for cutaneous wound healing and angiogenesis.

The inhibitor of angiogenesis, thrombospondin 2 (TSP2), belongs to a group of matricellular proteins that are induced in response to injury and modulate the healing of dermal wounds. Thus, TSP-2-null mice display abnormal connective tissue architecture and increased angiogenesis in the dermis, and heal wounds at an accelerated rate. In this study, we report that the content of TSP2 is increased in the uninjured skin of aged mice.

A comparative morphological study in 33 cases of respiratory chain encephalomyopathies.

Mitochondrial encephalomyopathies (ME) are clinically and genetically heterogeneous syndromes ranging from pure myopathies to complex multisystem disorders. This phenotypic and genotypic variability, coupled with the lack of a laboratory gold standard marker for the diseases, makes diagnosis a challenging process. Mitochondrial DNA analysis and biochemical assay of muscle homogenates are quite specific diagnostically but have low sensitivity in unselected cases suspected of ME.

Matricellular proteins as modulators of wound healing and the foreign body response.

Matricellular proteins form a group of extracellular matrix (ECM) proteins that do not subserve a primary structural role, but rather function as modulators of cell-matrix interactions. Members of the group, including thrombospondin (TSP)-1,TSP-2, SPARC, tenascin (TN)-C, and osteopontin (OPN), have been shown to participate in a number of processes related to tissue repair. Specifically, studies in knockout mice have indicated that a deficiency in one or more of these proteins can alter the course of wound healing.

Click evoked neurogenic vestibular potentials (NVESTEPs): a method of assessing the function of the vestibular system.

Objectives: To obtain neurogenic vestibular evoked potentials (NVESTEPs) with surface scalp recording using high intensity auditory clicks. The same stimulus is used in myogenic vestibular evoked potentials which has been shown to evoke potentials in the vestibular division of the vestibulocochlear nerve.

Methods: A whole head recording with surface EEG electrodes was performed using high intensity clicks in one normal volunteer to determine the best recording position for vestibular evoked potentials.

An open-label randomized clinical trial of novel therapeutic strategies for HIV-infected patients in whom antiretroviral therapy has failed: rationale and design of the OPTIMA Trial.

OPTIMA (OPTions In Management with Antiretrovirals) is a clinical trial with a factorial randomization to evaluate the hypotheses that mega-antiretroviral therapy (ART) consisting of five or more anti-HIV drugs compared to standard-ART consisting of four or fewer anti-HIV drugs and a 3-month antiretroviral drug-free period (ARDFP) compared to no ARDFP will delay the occurrence of new or recurrent acquired immunodeficiency syndrome events or death, and prove to be more cost-effective in treating human immunodeficiency virus-infected individuals previously exposed to ART drugs from the current three main classes. The aim is to randomize 1,700 participants to four treatment strategy arms: (1) ARDFP+standard-ART; (2) ARDFP+mega-ART; (3) no ARDFP+standard-ART; (4) no ARDFP+mega-ART. The planned study duration is 3.

Compressive lumbar myelopathy presenting as segmental motor neuron disease.

Four patients presented with slowly progressive, bilateral, asymmetric weakness and muscle atrophy in the lower extremities, accompanied by cramps and fasciculations. Sensory symptoms were insignificant. There was no bladder or bowel disturbance.

Megakaryocytes require thrombospondin-2 for normal platelet formation and function.

Mice that lack the matricellular angiogenesis inhibitor, thrombospondin-2 (TSP2), display a bleeding diathesis, despite normal blood coagulation and the lack of thrombocytopenia. Although platelets do not contain detectable levels of TSP2, TSP2-null platelets are compromised in their ability to aggregate in vivo in response to denudation of the carotid artery endothelium, and in vitro following exposure to adenosine diphosphate (ADP). Megakaryocytes (MKs) show high levels of TSP2 by immunohistochemical analysis of bone marrow.

Compromised production of extracellular matrix in mice lacking secreted protein, acidic and rich in cysteine (SPARC) leads to a reduced foreign body reaction to implanted biomaterials.

SPARC (secreted protein, acidic and rich in cysteine), a matricellular glycoprotein, modulates the interaction of cells with the extracellular matrix (ECM). Recently, accelerated cutaneous wound closure and altered deposition of collagen were reported in SPARC-null mice. Herein we asked whether SPARC might influence the foreign body reaction to biomaterial implants.

A novel NF-L mutation Pro22Ser is associated with CMT2 in a large Slovenian family.

Charcot-Marie-Tooth (CMT) disease is the most-common form of inherited motor and sensory neuropathy. The autosomal dominant axonal form of the disease (CMT2) is currently subdivided into seven types based on genetic localization. These are CMT2A (1p35-p36), CMT2B (3q13-q22), CMT2C (unknown), CMT2D (7p14), CMT2E (8p21), HMNSP (3q13.

The lack of thrombospondin-1 (TSP1) dictates the course of wound healing in double-TSP1/TSP2-null mice.

Thrombospondin (TSP) 1 and 2, share the same overall structure and interact with a number of the same cell-surface receptors. In an attempt to elucidate their biological roles more clearly, we generated double-TSP1/TSP2-null animals and compared their phenotype to those of TSP1- and TSP2-null mice. Double-null mice exhibited an apparent phenotype that primarily represented the sum of the abnormalities observed in the single-null mice.